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Curcumin enhances the effect of cisplatin in suppression of head and neck squamous cell carcinoma via inhibition of IKK? protein of the NF?B pathway.

ABSTRACT: Previous experiments have shown that curcumin or cisplatin treatment suppresses growth of head and neck squamous cell carcinoma (HNSCC). To study the potential cooperative effect of both agents, two HNSCC cell lines were treated with curcumin or cisplatin alone or in combination. In vivo studies consisted of intravenous tail vein injection of liposomal curcumin, with intraperitoneal cisplatin, into nude mice growing xenograft HNSCC tumors. Introduction of curcumin and suboptimal concentrations of cisplatin showed a significant suppressive effect compared with treatment with either agent alone. Reduced expression of cyclin D1, I?B?, phospho-I?B?, and IKK? occurred in cisplatin- and curcumin-treated cell lines. Confocal microscopy showed expression of IKK? in the nucleus of the cell lines. Chromatin immunoprecipitation assay on DNA isolated from IKK? immunoprecipitated samples showed PCR amplification of interleukin-8 promoter sequences, a binding site of NF?B, indicating an interaction between IKK? and NF?B. Curcumin inhibited IKK? in the cytoplasm and nucleus, leading to reduced NF?B activity, with no effect on phospho-AKT. In vivo studies showed significant growth inhibition of xenograft tumors treated with a combination of liposomal curcumin and cisplatin. The suppressive effect of curcumin was mediated through inhibition of cytoplasmic and nuclear IKK?, resulting in inhibition of NF?B activity. Cisplatin treatment led to cellular senescence, indicating an effect mediated by p53 activation. The mechanisms of the two agents through different growth signaling pathways suggest potential for the clinical use of subtherapeutic doses of cisplatin in combination with curcumin, which will allow effective suppression of tumor growth while minimizing the toxic side effects of cisplatin.

SUBMITTER: Duarte VM

PROVIDER: S-EPMC3004013 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Curcumin enhances the effect of cisplatin in suppression of head and neck squamous cell carcinoma via inhibition of IKKβ protein of the NFκB pathway.

Duarte Victor M VM Han Eugene E Veena Mysore S MS Salvado Amanda A Suh Jeffrey D JD Liang Li-Jung LJ Faull Kym F KF Srivatsan Eri S ES Wang Marilene B MB

Molecular cancer therapeutics 20101001 10

Previous experiments have shown that curcumin or cisplatin treatment suppresses growth of head and neck squamous cell carcinoma (HNSCC). To study the potential cooperative effect of both agents, two HNSCC cell lines were treated with curcumin or cisplatin alone or in combination. In vivo studies consisted of intravenous tail vein injection of liposomal curcumin, with intraperitoneal cisplatin, into nude mice growing xenograft HNSCC tumors. Introduction of curcumin and suboptimal concentrations o ...[more]

PMID: 20937593

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Project description:The inhibitor-?B kinase-nuclear factor-?B (IKK-NF-?B) and epidermal growth factor receptor-activator protein-1 (EGFR-AP1) pathways are often co-activated and promote malignant behavior, but the underlying basis for this relationship is unclear. Resistance to inhibitors of IKK? or EGFR is observed in head and neck squamous cell carcinomas (HNSCC). Here, we reveal that both IKK? and ? contribute to nuclear activation of canonical and alternate NF-?B/REL family transcription factors, and overexpression of signal components that enhance co-activation of the EGFR-AP1 pathway. We observed that IKK? and IKK? exhibit increased protein expression, nuclear localization, and phosphorylation in HNSCC tissues and cell lines. Individually, IKK activity varied among different cell lines, but overexpression of both IKKs induced the strongest NF-?B activation. Conversely, siRNA knock down of both IKKs significantly decreased nuclear localization and phosphorylation of canonical RELA and I?B? and alternative p52 and RELB subunits. Knock down of both IKKs more effectively inhibited NF-?B activation, broadly modulated gene expression and suppressed cell proliferation and migration. Global expression profiling revealed that NF-?B, cytokine, inflammatory response and growth factor signaling are among the top pathways and networks regulated by IKKs. Importantly, IKK? and IKK? together promoted the expression and activity of transforming growth factor ?, EGFR and AP1 transcription factors cJun, JunB and Fra1. Knock down of AP1 subunits individually decreased 8/15 (53%) of IKK-targeted genes sampled and similarly inhibited cell proliferation and migration. Mutations of NF-?B and AP1-binding sites abolished or decreased IKK-induced interleukin-8 (IL-8) promoter activity. Compounds such as wedelactone with dual IKK inhibitory activity and geldanomycins that block IKK?/? and EGFR pathways were more active than IKK?-specific inhibitors in suppressing NF-?B activation and proliferation and inducing cell death. We conclude that IKK? and IKK? cooperatively activate NF-?B and EGFR/AP1 networks of signaling pathways and contribute to the malignant phenotype and the intrinsic or acquired therapeutic resistance of HNSCC.

Dataset Information

Curcumin enhances the effect of cisplatin in suppression of head and neck squamous cell carcinoma via inhibition of IKK? protein of the NF?B pathway.

Publications

Curcumin enhances the effect of cisplatin in suppression of head and neck squamous cell carcinoma via inhibition of IKKβ protein of the NFκB pathway.

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